Nephrotoxicity after PRRT with <Superscript>177</Superscript>Lu-DOTA-octreotate

Purpose

After peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with ⁹⁰Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]-Octreotate (¹⁷⁷Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with ⁹⁰Y-radiolabelled somatostatin analogues.

Methods

The annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.

Results

Of the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5?–?3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (±?SD) was 108?±?5 ml/min and the estimated average annual decrease in CLR (±?SD) was 3.4?±?0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1?±?4.9 Gy.

Conclusion

Nephrotoxicity in patients treated with ¹⁷⁷Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with ⁹⁰Y-labelled somatostatin analogues, does not seem valid for PRRT with ¹⁷⁷Lu-octreotate.

     

Long-term results and tolerability of tandem peptide receptor radionuclide therapy with <Superscript>90</Superscript>Y/<Superscript>177</Superscript>Lu-DOTATATE in neuroendocrine tumors with respect to the primary location: a 10-year study

Introduction

The peptide receptor radionuclide therapy (PRRT) with ⁹⁰Y and ¹⁷⁷Lu is a form of molecular targeted therapy for inoperable or disseminated neuroendocrine tumors (NET).

Aim

The aim of the study was to evaluate clinical results and long-term side effects of tandem ⁹⁰Y /¹⁷⁷Lu-DOTATATE therapy in patients with NET. Additionally, we evaluated clinical results with reference to the primary site.

Materials and methods

59 patients with disseminated NET were included in the study prospectively. 3–5 cycles of combined 1:1 ⁹⁰Y/¹⁷⁷Lu-DOTATATE (total injected activity 11.1–16.65 GBq) with mixed amino acids for kidney protection were performed.

Results

During a median follow-up of 75.8 months, the PFS was 32.2 months, and the OS was 82 months; 25 patients died. Depending on primary tumor’s site, the PFS and the OS for pancreatic NET vs. small bowel, NET vs. large bowel, NET were 30.4 vs. 29.5 vs. 40.3 and 78.9 vs. 58.1 vs. 82.5, respectively. The observed 5-year overall survival was 63%, and a 2-year risk of progression was 39.4%. The following imaging response was observed: CR in 2%, PR in 22%, SD in 65%, and PD in 6% patients. The disease control rate was 89%. The objective response rate was 24%. The PRRT was well tolerated by all patients. One patient (2%) revealed MDS, and one patient (2%) grade 3 nephrotoxicity. No other grade 3 and 4 hematological or renal toxicity was observed.

Conclusions

These results indicated the tandem ⁹⁰Y/¹⁷⁷Lu-DOTATATE therapy for patients with disseminated/inoperable NET as highly effective and safe, considering long-term side effects. In the majority of patients, clinical improvement was observed.

     

The utility of PET/CT with <Superscript>68</Superscript>Ga-DOTATOC in sarcoidosis: comparison with <Superscript>67</Superscript>Ga-scintigraphy

Objective

This study was designed to compare the clinical efficacy of ⁶⁸Ga-DOTA-Tyr-octreotide (DOTATOC)-positron emission tomography (PET)/computed tomography (CT) with that of conventional ⁶⁷Ga-scintigraphy (GS), and to correlate quantitative parameters on DOTATOC-PET/CT with clinical data, in patients with sarcoidosis.

Methods

Twenty patients who were histologically and/or clinically diagnosed with sarcoidosis and underwent both DOTATOC-PET/CT and GS were analyzed in this study. The numbers of patients with positive findings for each organ were determined. The total numbers of involved nodal areas in the chest, as determined by DOTATOC-PET and gallium single-photon emission tomography (Ga-SPECT), were compared. The correlations between quantitative parameters on PET and clinical laboratory data were evaluated.

Results

DOTATOC-PET/CT was positive in 19 patients, being negative in only one patient with chronic inactive sarcoidosis, whereas GS was positive in 17 patients. DOTATOC-PET/CT visualized more lesions in lymph nodes, uvea, and muscles than did Ga-scintigraphy and identified more involved areas than did GS-SPECT (p < 0.0001). Whole-body active lesion volume showed a significant, but moderate correlation with angiotensin-converting enzyme level (ρ = 0.64, p = 0.0044).

Conclusions

PET/CT with DOTATOC may be superior to conventional GS in detecting sarcoidosis lesions, especially in lymph nodes, uvea, and muscles. Volumetric parameters in DOTATOC-PET/CT may be helpful in estimating the activity of sarcoidosis.

     

Subacute haematotoxicity after PRRT with <Superscript>177</Superscript>Lu-DOTA-octreotate: prognostic factors,incidence and course

Purpose

In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from ¹³¹I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit.

Methods

The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined.

Results

Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0?×?10⁹/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67?±?7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq ¹⁷⁷Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients.

Conclusion

The incidence of subacute haematological toxicity after PRRT with ¹⁷⁷Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from ¹³¹I, seems not to be valid for PRRT with ¹⁷⁷Lu-DOTATATE.

     

Molecular response assessed by <Superscript>68</Superscript>Ga-DOTANOC and survival after <Superscript>90</Superscript>Y microsphere therapy in patients with liver metastases from neuroendocrine tumours

Purpose

We investigated the prognostic role of ⁶⁸Ga-DOTANOC in patients affected by hepatic metastases from neuroendocrine tumours (NET) undergoing ⁹⁰Y radioembolization (⁹⁰Y-RE).

Methods

A group of 15 consecutive patients with unresectable NET liver metastases underwent ⁶⁸Ga-DOTANOC PET at baseline and 6 weeks after ⁹⁰Y-RE. Molecular response was defined as a reduction of >50 % in the tumour-to-spleen ratio (ΔT/S). The patients were divided into two groups (responders with ΔT/S >50 % and nonresponders with ΔT/S <50 %) Patients were followed up by imaging and laboratory tests every 3 months until death or for at least 36 months following ⁹⁰Y-RE. Statistical analysis was performed to identify factors predicting overall survival (OS) and progression-free survival (PFS).

Results

A decrease in T/S ratio was seen in all patients on ⁶⁸Ga-DOTANOC PET scans performed after ⁹⁰Y-RE. Nine patients were classified as responders and six as nonresponders. The mean OS in all patients was 31.0 months. Responders had a significantly (p?<?0.001) longer OS (mean 36.0?±?2.5 months) and PFS (mean 29.7?±?3.4 months) than nonresponders. In a multivariate analysis, none of the other examined variables including age, unilobar vs. bilobar locations, bilirubin levels, radiological response or the presence of extrahepatic disease significantly predicted patient outcome.

Conclusion

Molecular response assessed with ⁶⁸Ga-DOTANOC PET might be a useful predictor of survival in patients affected by NET liver metastases treated with ⁹⁰Y-RE.

     

Diagnostic and prognostic value of <Superscript>18</Superscript>F-FDG PET/CT for axillary lymph node staging in patients with breast cancer

Purpose

To investigate the diagnostic and prognostic value of ¹⁸F-FDG-PET/CT for axillary lymph node (LN) staging in breast cancer patients, employing histologic evaluation as the reference.

Methods

Among 196 patients with biopsy-proven breast cancer who had undergone ¹⁸F-FDG-PET/CT before mastectomy or breast-conserving surgery with sentinel LN biopsy and/or axillary LN dissection, 200 axillae were retrospectively analyzed by visual assessment and quantitatively using SUVmax. LN SUVmax as well as other clinicopathological features were assessed for their prognostic value using the log-rank test and Cox method.

Results

Metastasis was diagnosed histopathologically in 56 (28 %) axillae. The sensitivity, specificity, and accuracy of visual PET/CT for diagnosing node metastasis were 55.4, 95.8, and 84.5 %, respectively. When the optimal discriminative SUVmax cutoff was 1.5, these figures were 51.8, 97.2, and 84.5 %, respectively. Fourteen of 55 patients (25.5 %) with LN metastases suffered a recurrence during follow-up (median 39 months). Patients with a high nodal SUVmax (≥1.7) had a significantly lower progression-free survival rate than those with a low SUVmax (p = 0.0499). Axillary nodal and primary tumor SUVmax as well as estrogen receptor status were significantly associated with recurrence.

Conclusion

Axillary nodal SUVmax may be a prognostic indicator of disease recurrence in patients with axillary LN metastases.

     

A MAA-based dosimetric study in patients with intrahepatic cholangiocarcinoma treated with a combination of chemotherapy and <Superscript>90</Superscript>Y-loaded glass microsphere selective internal radiation therapy

Purpose

Selective internal radiation therapy (SIRT) appears to be an interesting treatment possibility for locally-advanced intrahepatic cholangiocarcinoma (ICC), yet the appropriate dosimetry has never been evaluated in this context.

Methods

We retrospectively studied data from 40 patients treated at our institution with ⁹⁰Y-loaded glass microsphere SIRT combined with chemotherapy for inoperable ICC as first-line treatment. Macroaggregated albumin (MAA)-based single-photon emission computed tomography (SPECT)/computed tomography (CT) quantitative analysis was used to calculate the tumor dose (TD), healthy-injected liver dose (HILD), and injected liver dose (ILD). Response was evaluated at 3 months using the European Association for the Study of the Liver criteria. Factors associated with response and toxicity were analyzed using univariate analysis.

Results

We assessed a total of 35 patients (five excluded) receiving 55 injections. Mean TD was 322?±?165Gy and mean HILD was 74?±?24Gy for a mean ILD of 128?±?28Gy. All but two lesions responded, with a minimal TD for responding lesions of 158Gy. Six Grade 3–4 permanent liver toxicities were observed. Mean HILD was not associated with liver toxicity (73.2?±?25.8Gy for patients with liver toxicity and 77.8?±?16.9Gy for patients without, ns). Only underlying Child-Pugh status (p?=?0.0014) and underlying cirrhosis (p?=?0.0021) were associated with liver toxicity. Median progression-free survival was 12.7 months and median overall survival (OS) was 28.6 months. Median OS was 52.7 months for patients with Child-Pugh A5 status.

Conclusions

When combined with chemotherapy, SIRT is highly effective, with a TD?>?158Gy. Tolerance was good except for the few patients with cirrhosis or Child-Pugh status ≥A6, who exhibited some liver toxicity. Prospective studies are warranted to confirm.

     

Robust evidence for long-term survival with <Superscript>90</Superscript>Y radioembolization in chemorefractory liver-predominant metastatic colorectal cancer

Objectives

Our aim was to provide further evidence for the efficacy/safety of radioembolization using yttrium-90-resin microspheres for unresectable chemorefractory liver metastases from colorectal cancer (mCRC).

Methods

We followed 104 consecutively treated patients until death. Overall survival (OS) was calculated from the day of the first radioembolization procedure. Response was defined by changes in tumour volume as defined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.0 and/or a ≥30 % reduction in serum carcinoembryonic antigen (CEA) at 3 months.

Results

Survival varied between 23 months in patients who had a complete response to prior chemotherapy and 13 months in patients with a partial response or stable disease. Median OS also significantly improved (from 5.8 months to 17.1 months) if response durability to radioembolization extended beyond 6 months. Patients with a positive trend in CEA serum levels (≥30 % reduction) at 3 months post-radioembolization also had a survival advantage compared with those who did not: 15.0 vs 6.7 months. Radioembolization was well tolerated. Grade 3 increases in bilirubin were reported in 5.0 % of patients at 3 months postprocedure.

Conclusions

After multiple chemotherapies, many patients still have a good performance status and are eligible for radioembolization. This single procedure can achieve meaningful survivals and is generally well tolerated.

Key Points

? After multiple chemotherapies, many patients are still eligible for radioembolization (RE). ? RE can achieve meaningful survival in patients with chemorefractory liver-predominant metastatic colorectal cancer (mCRC). ? Tumour responsiveness to prior systemic treatments is a significant determinant of overall survival (OS) after RE. ? Radioembolization in patients with a good performance status is generally well tolerated.

     

Individualised <Superscript>177</Superscript>Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry

Purpose

To present data from an interim analysis of a Phase II trial designed to determine the feasibility, safety, and efficacy of individualising treatment based on renal dosimetry, by giving as many cycles as possible within a maximum renal biologically effective dose (BED).

Method

Treatment was given with repeated cycles of 7.4 GBq ¹⁷⁷Lu-DOTATATE at 8-12-week intervals. Detailed dosimetry was performed in all patients after each cycle using a hybrid method (SPECT?+?planar imaging). All patients received treatment up to a renal BED of 27?±?2 Gy (α/β?=?2.6 Gy) (Step 1). Selected patients were offered further treatment up to a renal BED of 40?±?2 Gy (Step 2). Renal function was followed by estimation and measurement of the glomerular filtration rate (GFR).

Results

Fifty-one patients were included in the present analysis. Among the patients who received treatment as planned, the median number of cycles in Step 1 was 5 (range 3-7), and for those who completed Step 2 it was 7 (range 5-8); 73% were able to receive >4 cycles. Although GFR decreased in most patients after the completion of treatment, no grade 3-4 toxicity was observed. Patients with a reduced baseline GFR seemed to have an increased risk of GFR decline. Five patients received treatment in Step 2, none of whom exhibited a significant reduction in renal function.

Conclusions

Individualising PRRT using renal dosimetry seems feasible and safe and leads to an increased number of cycles in the majority of patients. The trial will continue as planned.

     

Prediction of all-cause death using <Superscript>11</Superscript>C-hydroxyephedrine positron emission tomography in Japanese patients with left ventricular dysfunction

Objectives

The aim of this study was to determine whether ¹¹C-hydroxyephedrine (¹¹C-HED) can predict adverse events including all-cause death in Japanese patients with left ventricular (LV) dysfunction.

Background

Although ¹¹C-HED PET has been used to assess cardiac sympathetic innervation in various disease conditions, data on their prognostic value are limited.

Methods

Sixty patients (mean LVEF, 42 ± 14 %) with LV dysfunction (42 ischemic and 18 non-ischemic heart disease) underwent ¹¹C-HED PET. Myocardial retention was calculated for ¹¹C-HED PET as a measure of cardiac sympathetic neuronal integrity. Statistical analysis was performed using Cox proportional hazards regression and log-rank test.

Results

Thirteen deaths (7 cardiac and 6 non-cardiac deaths) occurred during a mean follow-up period of 33 ± 23 months. The patients with death were associated with significantly lower ¹¹C-HED retention (7.1 ± 2.1 vs 9.0 ± 2.4, p = 0.015) than those without death. The hazard ratio for global ¹¹C-HED retention per unit (/min) was 0.762 (p = 0.039), which remained significant in multivariate analysis. When the patients were divided into the high (≥8.5) and low (<8.5) ¹¹C-HED retention groups, the low ¹¹C-HED retention group was associated with significantly poorer survival than the high ¹¹C-HED retention group (p = 0.004).

Conclusion

The low global ¹¹C-HED retention is a marker of poor overall survival in patients with LV dysfunction in this study.

     

Utility of <Superscript>18</Superscript>F-fluoroestradiol (<Superscript>18</Superscript>F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy

Background

Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. ¹⁸F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes ¹⁸F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen.

Methods

Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with ¹⁸F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with ¹⁸F-FES 1–5 days post administration of Z-endoxifen.

Results

Statistically significant changes (p?=?0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration.

Conclusion

F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

     

<Superscript>18</Superscript>F-FDG uptake by rectal cancer is similar in mucinous and nonmucinous histological subtypes

Purpose

PET/CT has been considered limited for the evaluation of mucinous colorectal tumors due to low ¹⁸F-FDG uptake. The aim of our study was to compare PET/CT variables in mucinous (MC) and nonmucinous (NMC) rectal adenocarcinomas.

Methods

Consecutive patients with cT2-4N0-2M0 rectal cancer included in a prospective clinical trial were reviewed. PET/CT was performed for primary baseline staging. Visual and quantitative analysis included SUVmax and SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG). PET/CT parameters were compared according to histological subtypes.

Results

Overall, 73 patients were included (18 mucinous and 55 nonmucinous). SUVmax values were similar between MC and NMC (19.7 vs. 16.6; p = 0.5). MTV and TLG values were greater in the MC group (103.9 vs. 54.1; p = 0.007 and 892.5 vs. 358.8; p = 0.020) due to larger tumor volumes of MC.

Conclusions

Metabolic parameters at baseline PET/CT for patients with rectal cancer are similar in mucinous and nonmucinous histological subtypes.

     

Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity <Superscript>86</Superscript>Y- or <Superscript>177</Superscript>Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

Purpose

GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn–(radiolanthanide metal) complex.

Methods

PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens ¹⁷⁷Lu-or ⁸⁶Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model.

Results

Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq ¹⁷⁷Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 – 700 mm³) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 – 3.0 based on time to 500-mm³ tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten ⁸⁶Y-DOTA-Bn.

Conclusion

We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts.

     

Delayed response after repeated <Superscript>177</Superscript>Lu-PSMA-617 radioligand therapy in patients with metastatic castration resistant prostate cancer

Purpose

Radioligand therapy (RLT) using Lutetium-177 labeled PSMA-617 (Lu-PSMA) ligand is a new therapeutic option for salvage therapy in heavily pretreated patients with metastatic castration resistant prostate cancer. The aim of this retrospective study was to analyze response in patients receiving 3 cycles of Lu-PSMA.

Methods

Seventy-one patients (median age: 72 years; range 44–87) received 3 cycles of RLT with Lu-PSMA (mean administered activity: 6.016 ± 0.543 GBq) every 8 weeks. Response was evaluated using serum PSA levels and a PSA decline ≥50% was considered as biochemical response. Additionally, any PSA decline after the first cycle was evaluated for further therapy effects after the second and third cycle.

Results

A total of 213 cycles were performed in 71 patients. Data for response and adverse events were available for all patients. A PSA decline ≥50% and some PSA decline occurred in 56% and 66% of the patients. Of 30 patients with a PSA response after the first cycle, 28 remained responders and 12/41 of non-responders responded to further therapy cycles.

Conclusion

RLT with Lu-177-PSMA-617 shows respectable response rates. In this retrospective analysis, a relevant number of patients showed a delayed response, even if they did not respond to the first cycle of the therapy.

     

Multimodal imaging with <Superscript>18</Superscript>F-FDG-PET/CT and <Superscript>111</Superscript>In-Octreotide SPECT in patients with metastatic medullary thyroid carcinoma

Objective

The aim of our study was to determine the role of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) and indium-111 Octreotide single photon emission tomography (¹¹¹In-Octreotide SPECT) in the evaluation of metastatic medullary thyroid carcinoma (MMTC).

Methods

Twenty-five MMTC patients were retrospectively evaluated. All patients had undergone whole-body ¹⁸F-FDG-PET/CT including 20 who had also undergone ¹¹¹In-Octreotide SPECT within a maximum interval of 6 weeks. Diagnostic contrast-enhanced computed tomography (CT) alone or as part of ¹⁸F-FDG-PET/CT examination was performed in all patients.

Results

Contrast-enhanced CT detected a total of 131 lesions including 79 enlarged lymph nodes and 14 bone lesions. ¹⁸F-FDG-PET/CT visualized a total of 92 true positive lesions (SUV_max range 1.1–10.0, mean 4.0 ± 1.7) including 66 lymph nodes, 7 of which were not enlarged on CT, and 8 bone metastases. In the 20 patients studied with both techniques, a total of 64 and 46 true positive lesions were detected by ¹⁸F-FDG-PET/CT and ¹¹¹In-Octreotide SPECT, respectively. In particular, ¹⁸F-FDG uptake was found in 43 lymph nodes and in 7 bone metastases whereas ¹¹¹In-Octreotide uptake was detected in 27 lymph nodes and in 10 bone metastases.

Conclusions

In MMTC patients, ¹⁸F-FDG-PET/CT provides a useful contribution mainly in evaluating lymph node involvement whereas ¹¹¹In-Octreotide SPECT can contribute to the detection and somatostatin receptor characterization especially of bone lesions.

     

Radiation dosimetry of <Superscript>68</Superscript>Ga-PSMA-11 (HBED-CC) and preliminary evaluation of optimal imaging timing

Purpose

The clinical introduction of ⁶⁸Ga-PSMA-11 (“HBED-CC”) ligand targeting the prostate-specific membrane antigen (PSMA) has been regarded as a significant step forward in the diagnosis of prostate cancer (PCa). In this study, we provide human dosimetry and data on optimal timing of PET imaging after injection.

Methods

Four patients with recurrent PCa were referred for ⁶⁸Ga-PSMA-11 PET/CT. Whole-body PET/CT_low-dose scans were conducted at 5 min, and 1, 2, 3, 4 and 5 h after injection of 152–198 MBq ⁶⁸Ga-PSMA-11. Organs of moderate to high uptake were used as source organs; their total activity was determined at all measured time points. Time–activity curves were created for each source organ as well as for the remainder. The radiation exposure of a ⁶⁸Ga-PSMA-11 PET was identified using the OLINDA-EXM software. In addition, tracer uptake was measured in 16 sites of metastases.

Results

The highest tracer uptake was observed in the kidneys, liver, upper large intestine, and the urinary bladder. Mean organ doses were: kidneys 0.262?±?0.098 mGy/MBq, liver 0.031?±?0.004 mGy/MBq, upper large intestine 0.054?±?0.041 mGy/MBq, urinary bladder 0.13?±?0.059 mGy/MBq. The calculated mean effective dose was 0.023?±?0.004 mSv/MBq (=0.085?±?0.015 rem/mCi). Most tumor lesions (n?=?16) were visible at 3 h p.i., while at all other time points many were not qualitatively present (10/16 visible at 1 h p.i.).

Conclusions

The mean effective dose of a ⁶⁸Ga-PSMA-11 PET is 0.023 mSv/MBq. A 3-h delay after injection was optimal timing for ⁶⁸Ga-PSMA-11 PET/CT in this patient cohort.

     

Dual-time-point <Superscript>18</Superscript>F-FDG PET/CT in the diagnosis of solitary pulmonary lesions in a region with endemic granulomatous diseases

Objective

Granulomatous diseases (GDs) can be metabolically active and indistinguishable from lung cancer on ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) imaging. Evaluation of solitary pulmonary lesions remains a diagnostic challenge in regions with endemic GD. This study sought to determine the efficacy of dual-time-point (DTP) ¹⁸F-FDG PET/computed tomography (CT) imaging in diagnosing solitary pulmonary lesions from such regions.

Methods

A total of 50 patients with solitary pulmonary nodules or masses with confirmed histopathological diagnoses underwent DTP ¹⁸F-FDG PET/CT imaging at 1 and 3 h after tracer injection. The maximum standardized uptake value (SUV_max) on early and delayed scans (SUV_1h and SUV_3h, respectively) and retention index (RI) were calculated for each pulmonary lesion. Receiver operating characteristic analysis was performed to evaluate the discriminating validity of the parameters.

Results

There were 37 malignant and 13 benign solitary pulmonary lesions. Eight of the 13 (62 %) benign lesions were GDs. The sensitivity/specificity/accuracy of SUV_1h, SUV_3h and RI were 84/69/80 %, 84/85/84 %, and 81/54/74 %, respectively. SUV_3h had the best diagnostic performance, especially regarding specificity. The values of SUV_1h and SUV_3h were significantly different between malignant lesions and GD, while the RI values of malignant lesions and GD were both high (18.6 ± 19.5 and 18.7 ± 15.3 %, respectively; P = not significant).

Conclusion

SUV_3h appeared to improve the diagnostic specificity of ¹⁸F-FDG PET/CT in evaluating solitary pulmonary lesions from regions with endemic GD.

     

Perfusion and metabolic scintigraphy with <Superscript>123</Superscript>I-BMIPP in prognosis of cardiac resynchronization therapy in patients with dilated cardiomyopathy

Objective

The objective of the study was to investigate the left ventricular (LV) myocardial perfusion and metabolism in patients with idiopathic dilated cardiomyopathy (DCM) and to identify the scintigraphic predictors of the efficacy of cardiac resynchronization therapy (CRT).

Methods

The study comprised 63 patients with DCM and severe heart failure (NYHA class III–IV). Before CRT, all patients received gamma-scintigraphy with ^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI) and with ¹²³I-β-methyl-iodophenyl pentadecanoic acid (¹²³I-BMIPP) for evaluation of myocardial perfusion and metabolism, respectively. Before and after 6 months of CRT, all patients underwent echocardiography study to assess cardiac hemodynamics.

Results

After 6 months of CRT, patients were divided into two groups: group 1 comprised responders in whom LV end systolic volume (LVESV) decreased by ≥15 % (n = 39); group 2 comprised non-responders in whom LVESV decreased by <15 % (n = 24). Before CRT, LV pumping function did not significantly differ between groups. Significant differences were found in the following preoperative scintigraphic parameters: myocardial perfusion defect size [7.4 % (5.9; 13.2) % and 11.8 (8.8; 16.2) %, p < 0.05] and metabolic defect size [7.4 (4.4; 14.7) % and 8.8 (8.8; 17.6) %, p < 0.05]. Metabolic scintigraphy showed greater diagnostic efficacy in determining the indications for CRT compared with perfusion scintigraphy [areas under the ROC curves (AUC) of 0.722 and 0.612, respectively]. The best metabolic defect size threshold value of 7.35 % predicted CRT efficacy with the sensitivity and specificity rates of 77.8 and 66.7 %, respectively.

Conclusion

Data of metabolic scintigraphy may be useful for the integrated prediction of CRT efficacy.

     

Molecular imaging of cholinergic processes in prostate cancer using <Superscript>11</Superscript>C-donepezil and <Superscript>18</Superscript>F-FEOBV

Purpose

High-grade prostate cancer (PC) displays parasympathetic neoneurogenesis. We investigated the binding of two PET tracers that visualize cholinergic nerves in PC tissue using autoradiography.

Methods

Prostatectomy tissue was subjected to autoradiography with ¹¹C-donepezil and ¹⁸F-FEOBV and correlated with Gleason scores (GS). Regions of interest on the autoradiograms were defined and quantified. Tracer binding in cancer tissue regions was compared with that in normal tissue.

Results

We included 13 patients with biopsy-verified PC. In particular, ¹¹C-donepezil uptake was higher in “high-grade” PC (GS ≥4?+?3) than in “low-grade” PC and benign hyperplasia. ¹¹C-donepezil uptake ranged from a mean of 56 % higher (GS 3?+?3) to 409 % higher (GS 4?+?4), and ¹⁸F-FEOBV uptake ranged from 67 % higher (GS 3?+?3) to 194 % higher (GS 4?+?5). The uptake of both tracers was higher in PC with a high GS than in PC with a low GS, but the difference was significant only for ¹¹C-donepezil (p?=?0.003).

Conclusion

Uptake of PET tracers binding to cholinergic nerves was markedly higher in PC with a high GS than in PC with a low GS. This finding implies that ¹¹C-donepezil PET/CT may be able to differentiate between low-grade and high-grade PC.

     

Phase I/II trials of <Superscript>186</Superscript>Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival

Purpose

To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit.

Methods

Clinical data from 57 patients who received 2.5–5.1 GBq of ¹⁸⁶Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan–Meier curves, log-rank tests, Cox’s proportional hazards model and Pearson’s correlation coefficients were used for overall survival (OS) and correlation analyses.

Results

A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10–0.58, P?=?0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r?=?0.65, P?=?0.001) and the whole-body absorbed dose (r?=?0.63, P?=?0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of ¹⁸⁶Re-HEDP (P?=?0.03) and patient mean absorbed dose (P?=?0.01), whilst only the disease volume remained significant in a multivariable analysis (P?=?0.004).

Conclusion

This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose–response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient-specific imaging and dosimetry.